Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor

Shusaku Uchida, Kumiko Hara, Ayumi Kobayashi, Mitsuaki Fujimoto, Koji Otsuki, Hirotaka Yamagata, Teruyuki Hobara, Naoko Abe, Fumihiro Higuchi, Tomohiko Shibata, Shunsuke Hasegawa, Satoshi Kida, Akira Nakai, Yoshifumi Watanabe

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1-/-) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1 -/- mice. In addition, HSF1-/- mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. Furthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid-neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1 -/- mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.

Original languageEnglish
Pages (from-to)1681-1686
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number4
DOIs
Publication statusPublished - 2011 Jan 25

Keywords

  • Emotion
  • Neuronal maturation
  • Polysialylation
  • Spine density

ASJC Scopus subject areas

  • General

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    Uchida, S., Hara, K., Kobayashi, A., Fujimoto, M., Otsuki, K., Yamagata, H., Hobara, T., Abe, N., Higuchi, F., Shibata, T., Hasegawa, S., Kida, S., Nakai, A., & Watanabe, Y. (2011). Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor. Proceedings of the National Academy of Sciences of the United States of America, 108(4), 1681-1686. https://doi.org/10.1073/pnas.1016424108